17-43051068-G-T

Position:

• chr17-43051068-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_007294.4(BRCA1):​c.5327C>A​(p.Pro1776His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3 O:1
• Conservation: PhyloP100: 1.94

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43051068-G-T is Benign according to our data. Variant chr17-43051068-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246175.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5327C>A	p.Pro1776His	missense_variant	20/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5327C>A	p.Pro1776His	missense_variant	20/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2023	This missense variant replaces proline with histidine at codon 1776 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a haploid cell proliferation assay and transcription activation, yeast colony size, homology-directed DNA repair and cisplatin resistance assays (PMID: 27272900, 29884841, 30209399, 35196514). This variant has been reported in at least two individuals affected with breast cancer (PMID: 18824701, 32885271) and it has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000454). Multifactorial analyses using tumor pathology, functional studies and family history have reported this variant to be likely not associated with disease (PMID: 18824701, 21990134, 33087888). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces proline with histidine at codon 1776 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a haploid cell proliferation assay and transcription activation, yeast colony size, homology-directed DNA repair and cisplatin resistance assays (PMID: 27272900, 29884841, 30209399, 35196514). This variant has been reported in at least two individuals affected with breast cancer (PMID: 18824701, 32885271) and it has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000454). Multifactorial analyses using tumor pathology, functional studies and family history have reported this variant to be likely not associated with disease (PMID: 18824701, 21990134, 33087888). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 18, 2023

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a large breast cancer association study in one individual with breast cancer (PMID: 33471991 (2021)). In one functional study, the variant was reported as functional (PMID: 30209399 (2018)), and in another study the variant behaved similar to the wild type BRCA1 protein (PMID: 27272900 (2016)). In addition, published multifactorial analyses have reported inconclusive results (PMID: 18824701 (2008), 31131967 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Pro1776His variant has been previously reported in the literature in several studies that use in silico models to assess the clinical significance of the variant (Lindor 2011, Rajasekaran 2007, Williams 2003), however, these studies had conflicting results and this information was not very predictive of pathogenicity. The variant was also identified in dbSNP (ID: rs398122695) as "With Uncertain significance, other allele ", in ClinVar (classified as likely benign by GeneDx; as uncertain significance by Ambry Genetics), LOVD 3.0, and ARUP Laboratories (likely not pathogenic or of little clinical significance). The variant was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, and Zhejiang University databases. The variant was identified in control databases in 1 of 246152 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in African population in 1 of 15280 chromosomes (freq: 0.00007), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Latino, Other, and South Asian populations. The p.Pro1776 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In addition, the functional assessment of genetic variants by Thouvenot (2016) in a colony size assay identified the probability of pathogenicity of the p.Pro1776His variant is 0.00475, and classified the variant as likely neutral. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.;T;T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.2	D;N;.;D;.;.;N;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D;D;.;D;.;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;D;.;.
Vest4		0.61
MVP		0.91
MPC		0.47
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.57
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398122695; hg19: chr17-41203085;